This invention relates to hydantoin compounds and methods of use thereof, and more particularly this invention relates to novel hydantoin compounds which have anti-tumor activity against transplanted mouse tumor test systems.
The design of drugs which have potential utility in the chemotherapy of tumors of the central nervous system contains numerous challenges. In addition to possessing antitumor activity, a potential anti-tumor agent should have structural features which allow it to circumvent natural defense mechanisms, such as the blood-brain-barrier (BBB). There appear to be significant differences in the anatomical structure of brain tumors and their surrounding areas compared to normal brain. While the neoplasm appears to alter the BBB in such a way that drug penetration is sometimes enhanced, the changes are not constant among different types of brain tumors. This indicates that the permeability properties are not altered to the same extent and the BBB is a factor which must be considered. The situation is complex and in seeking new anti-tumor drugs, one should be concerned with the type of structure which (a) penetrates the BBB (b) does so in significant concentrations and (c) has anti-tumor activity.
The principle of using a carrier for an anti-tumor active functional group, e.g. a nitrogen mustard, is not new, and phenylalanine mustard (sarcolysin) is an example of this application. In a recent review of CNS anti-tumor agents, Broder and Rall concluded that new drug emphasis should be placed on alkylating agents which are able to cross the BBB. The reports that 5,5-diphenylhydantoin penetrated the BBB in significant concentrations and localized in brain tumors relative to surrounding normal brain tissue but had no anti-tumor activity, prompted a study of hydantoins as carriers for nitrogen mustard groups in an attempt to prepare agents which might have utility as drugs for CNS and brain tumors. Mauger and Ross have previously used the hydantoin ring as a carrier in a series of active bis-2-chloroethylaminoaryl hydantoins which were tested against the Walker tumor system.